JP2012505238A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2012505238A5 JP2012505238A5 JP2011531180A JP2011531180A JP2012505238A5 JP 2012505238 A5 JP2012505238 A5 JP 2012505238A5 JP 2011531180 A JP2011531180 A JP 2011531180A JP 2011531180 A JP2011531180 A JP 2011531180A JP 2012505238 A5 JP2012505238 A5 JP 2012505238A5
- Authority
- JP
- Japan
- Prior art keywords
- item
- disorders
- compound
- bond
- gaba
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 claims description 78
- 150000001875 compounds Chemical class 0.000 claims description 63
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 48
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 208000035475 disorder Diseases 0.000 claims description 19
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 12
- 208000012902 Nervous system disease Diseases 0.000 claims description 12
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 230000000202 analgesic effect Effects 0.000 claims description 11
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 11
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 11
- 208000019022 Mood disease Diseases 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 9
- 230000001430 anti-depressive effect Effects 0.000 claims description 9
- 239000000935 antidepressant agent Substances 0.000 claims description 9
- 229940005513 antidepressants Drugs 0.000 claims description 9
- 229960001233 pregabalin Drugs 0.000 claims description 8
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 8
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 claims description 6
- 208000027520 Somatoform disease Diseases 0.000 claims description 6
- 229960000794 baclofen Drugs 0.000 claims description 6
- 229960002870 gabapentin Drugs 0.000 claims description 6
- 208000027753 pain disease Diseases 0.000 claims description 6
- 229960005318 vigabatrin Drugs 0.000 claims description 6
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 208000014644 Brain disease Diseases 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 5
- 206010010904 Convulsion Diseases 0.000 claims description 5
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 claims description 5
- 206010021143 Hypoxia Diseases 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 206010033864 Paranoia Diseases 0.000 claims description 5
- 208000027099 Paranoid disease Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 208000028017 Psychotic disease Diseases 0.000 claims description 5
- 208000005793 Restless legs syndrome Diseases 0.000 claims description 5
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 5
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 5
- 208000016620 Tourette disease Diseases 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 208000018459 dissociative disease Diseases 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 230000007954 hypoxia Effects 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 5
- 206010022437 insomnia Diseases 0.000 claims description 5
- 208000022821 personality disease Diseases 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 125000000626 sulfinic acid group Chemical group 0.000 claims description 5
- 206010042772 syncope Diseases 0.000 claims description 5
- -1 opioid Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims 2
- 231100000331 toxic Toxicity 0.000 claims 2
- 230000002588 toxic effect Effects 0.000 claims 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229960005181 morphine Drugs 0.000 claims 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
- 229960002009 naproxen Drugs 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 229940124597 therapeutic agent Drugs 0.000 description 10
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 8
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 4
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 4
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 4
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000001773 anti-convulsant effect Effects 0.000 description 4
- 230000000648 anti-parkinson Effects 0.000 description 4
- 230000000561 anti-psychotic effect Effects 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- 229960003965 antiepileptics Drugs 0.000 description 4
- 239000000939 antiparkinson agent Substances 0.000 description 4
- 239000002249 anxiolytic agent Substances 0.000 description 4
- 230000000949 anxiolytic effect Effects 0.000 description 4
- 239000000544 cholinesterase inhibitor Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 4
- 229960002748 norepinephrine Drugs 0.000 description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 4
- 208000017194 Affective disease Diseases 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000004968 inflammatory condition Effects 0.000 description 3
- 208000009132 Catalepsy Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
Description
さらに、本発明において、本発明の化合物または本発明の化合物の医薬組成物、およびキットを使用するための使用説明書を備える、被検体の疼痛または神経系障害を予防または処置するためのキットを提供する。一部の実施形態において、被検体は動物、好ましくはヒトである。他の実施形態では、キットは、さらに、疼痛または神経系障害の処置における使用のための、本発明の化合物によって誘導される副作用低減のための、および／または本発明の化合物の治療有効性の向上のための少なくとも１種類の他の薬剤を含む。
本発明は、例えば以下の項目を提供する。
（項目１）
第１部分と第２部分とを含む化合物であって、該第１部分はアミノ末端またはカルボン酸基以外の酸性末端によって該第２部分に共有結合され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である、化合物。
（項目２）
第１部分と第２部分とを含み、該第１部分はカルボン酸基によって該第２部分に共有結合され、該第１部分のアミノ末端は保護基に連結され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である化合物。
（項目３）
前記第１部分がＧＡＢＡ類似体である、項目１または２に記載の化合物。
（項目４）
前記第１部分が、バクロフェン、ビガバトリン、ガバペンチン、またはプレガバリン、またはγ−アミノホスフィン酸誘導体である、項目３に記載の化合物。
（項目５）
前記第２部分が鎮痛薬である、項目１または２に記載の化合物。
（項目６）
前記第２部分が、非ステロイド系抗炎症薬（ＮＳＡＩＤ）、オピオイド、または抗鬱薬である、項目５に記載の化合物。
（項目７）
前記第２部分が、γ−ヒドロキシ酪酸（ＧＨＢ）、またはＧＨＢの類似体、誘導体もしくは改変体である、項目１または２に記載の化合物。
（項目８）
前記第１および前記第２部分が、エステル結合、アミド結合、イミン結合、カルバメート結合、カーボネート結合、チオエステル結合、アシルオキシカルバメート結合、アシルオキシカーボネート結合、ホスフェート結合およびアシルオキシホスフェート結合からなる群より選択される共有結合によって連結されている、項目１または２に記載の化合物。
（項目９）
前記第１部分を前記第２部分に共有結合させるリンカーをさらに含む、項目１または２に記載の化合物。
（項目１０）
前記リンカーが生理学的に不安定である、項目９に記載の化合物。
（項目１１）
前記化合物の前記第１部分または第２部分にイオン結合または共有結合された第３部分をさらに含む、項目１または２に記載の化合物。
（項目１２）
少なくとも１種類の他の治療用薬剤と組み合わせて使用され得る、項目１または２に記載の化合物。
（項目１３）
前記治療用薬剤が、抗精神病薬、抗不安薬、抗鬱薬、抗痙攣薬、抗パーキンソン病薬、アセチルコリンエステラーゼ阻害薬、ＭＡＯ阻害薬、選択的セロトニン再取込み阻害薬（ＳＳＲＩ）、Ｎ−メチル−Ｄ−アスパラギン酸（ＮＭＤＡ）拮抗薬、および選択的ノルアドレナリン置換阻害薬からなる群より選択される、項目１２に記載の化合物。
（項目１４）
前記酸性末端がホスフィン酸基またはスルフィン酸基を含む、項目１に記載の化合物。
（項目１５）
前記保護基が、アミノ酸、イミン、カルバメート、Ｎ−ジチアスクシンイミド、モノ−もしくはジ−アルキルホスホルアミデート、またはアシルオキシカルバメートを含む、項目２に記載の化合物。
（項目１６）
前記保護基が前記第１部分のアミノ基から切断可能である、項目２に記載の化合物。
（項目１７）
項目１または２に記載の化合物と薬学的に許容され得る担体とを含む医薬組成物。
（項目１８）
少なくとも１種類の他の治療用薬剤をさらに含む、項目１７に記載の医薬組成物。
（項目１９）
疼痛および／または神経系障害を処置するためのものである、項目１７に記載の医薬組成物。
（項目２０）
被検体の疼痛または神経系障害を予防または処置するためのキットであって、項目１または２に記載の化合物、および該キットを使用するための使用説明書を備える、キット。
（項目２１）
前記被検体が動物、好ましくはヒトである、項目２０に記載のキット。
（項目２２）
疼痛または神経系障害の処置における使用のための少なくとも１種類の他の薬剤をさらに含む、項目２０に記載のキット。
（項目２３）
障害の予防または処置方法であって、該予防または処置を必要とする被検体に治療有効量の化合物を投与することを含み、該化合物が、第１部分と第２部分とを含み、該第１部分はアミノ末端またはカルボン酸基以外の酸性末端によって第２部分に共有結合され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である、方法。
（項目２４）
障害の予防または処置方法であって、該予防または処置を必要とする被検体に治療有効量の化合物を投与することを含み、該化合物が、第１部分と第２部分とを含み、該第１部分は、カルボン酸基によって第２部分に共有結合され、該第１部分のアミノ末端が保護基に連結され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である、方法。
（項目２５）
前記第１部分がＧＡＢＡ類似体である、項目２３または２４に記載の方法。
（項目２６）
前記第１部分が、バクロフェン、ビガバトリン、ガバペンチン、プレガバリン、またはγ−アミノホスフィン酸誘導体である、項目２３または２４に記載の方法。
（項目２７）
前記第２部分が鎮痛薬である、項目２３または２４に記載の方法。
（項目２８）
前記第２部分が、非ステロイド系抗炎症薬（ＮＳＡＩＤ）、オピオイド、または抗鬱薬である、項目２３または２４に記載の方法。
（項目２９）
前記第２部分が、γ−ヒドロキシ酪酸（ＧＨＢ）、またはＧＨＢの類似体、誘導体もしくは改変体である、項目２３または２４に記載の方法。
（項目３０）
前記第１および前記第２部分が、エステル結合、アミド結合、イミン結合、カルバメート結合、カーボネート結合、チオエステル結合、アシルオキシカルバメート結合、アシルオキシカーボネート結合、ホスフェート結合およびアシルオキシホスフェート結合からなる群より選択される共有結合によって連結されている、項目２３または２４に記載の方法。
（項目３１）
前記第１部分を前記第２部分に共有結合させるリンカーをさらに含む、項目２３または２４に記載の方法。
（項目３２）
前記リンカーが生理学的に不安定である、項目３１に記載の方法。
（項目３３）
前記化合物の第１部分または第２部分にイオン結合または共有結合された第３部分をさらに含む、項目２３または２４に記載の方法。
（項目３４）
前記化合物が少なくとも１種類の他の治療用薬剤と組み合わせて使用され得る、項目２３または２４に記載の方法。
（項目３５）
前記治療用薬剤が、抗精神病薬、抗不安薬、抗鬱薬、抗痙攣薬、抗パーキンソン病薬、アセチルコリンエステラーゼ阻害薬、ＭＡＯ阻害薬、選択的セロトニン再取込み阻害薬（ＳＳＲＩ）、Ｎ−メチル−Ｄ−アスパラギン酸（ＮＭＤＡ）拮抗薬、および選択的ノルアドレナリン置換阻害薬からなる群より選択される、項目３４に記載の方法。
（項目３６）
前記予防または処置を必要とする被検体に、前記化合物と薬学的に許容され得る担体とを含む医薬組成物の治療有効量を投与することをさらに含む、項目２３または２４に記載の方法。
（項目３７）
前記障害が疼痛または神経系障害である、項目２３または２４に記載の方法。
（項目３８）
疼痛が、急性、慢性または炎症性状態のものである、項目３７に記載の方法。
（項目３９）
前記神経系障害が、有痛障害、不安障害、鬱、解離性障害、人格障害、認知障害、気分障害、情動障害、神経変性障害、痙攣性障害、パーキンソン病、アルツハイマー病、癲癇、統合失調症、パラノイア、精神病、ハンティングトン病、ジル・ド・ラ・ツレット症候群、失神発作、運動低下症、脳障害、神経変性障害、パニック、不眠症、中毒性障害、および不穏下肢症候群からなる群より選択される、項目３７に記載の方法。
（項目４０）
前記被検体が動物である、項目２３または２４に記載の方法。
（項目４１）
前記被検体がヒトである、項目４０に記載の方法。
（項目４２）
前記化合物または前記医薬組成物の投与により、個々の部分単独の投与と比べて副作用が少なくとも１つ少なくなる、項目２３または２４に記載の方法。
（項目４３）
前記化合物または前記医薬組成物の投与により、個々の部分単独の投与と比べて治療活性の向上がもたらされる、項目２３または２４に記載の方法。
（項目４４）
前記化合物または前記医薬組成物が別の薬剤と組み合わせて投与される、項目２３または２４に記載の方法。
（項目４５）
前記別の薬剤が、前記化合物または前記医薬組成物の投与の前、同時または後に投与される、項目４４に記載の方法。
（項目４６）
前記酸性末端がホスフィン酸基またはスルフィン酸基を含む、項目２３に記載の方法。
（項目４７）
前記保護基が、アミノ酸、イミン、カルバメート、Ｎ−ジチアスクシンイミド、モノ−もしくはジ−アルキルホスホルアミデート、またはアシルオキシカルバメートを含む、項目２４に記載の方法。
（項目４８）
前記保護基が前記第１部分のアミノ基から切断可能である、項目２４に記載の方法。
（項目４９）
障害の処置と関連している有害作用の低減方法であって、該低減を必要とする被検体に、治療有効量の化合物を投与することを含み、該化合物が、第１部分と第２部分とを含み、該第１部分は、アミノ末端またはカルボン酸基以外の酸性末端によって該第２部分に共有結合され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である、方法。
（項目５０）
障害の処置と関連している有害作用の低減方法であって、該低減を必要とする被検体に治療有効量の化合物を投与することを含み、該化合物が、第１部分と第２部分とを含み、該第１部分は、カルボン酸基によって該第２部分に共有結合され、該第１部分のアミノ末端が保護基に連結され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である、方法。
（項目５１）
前記第１部分がＧＡＢＡ類似体である、項目４９または５０に記載の方法。
（項目５２）
前記第１部分が、バクロフェン、ビガバトリン、ガバペンチン、プレガバリン、またはγ−アミノホスフィン酸誘導体である、項目４９または５０に記載の方法。
（項目５３）
前記第２部分が鎮痛薬である、項目４９または５０に記載の方法。
（項目５４）
前記第２部分が、非ステロイド系抗炎症薬（ＮＳＡＩＤ）、オピオイド、または抗鬱薬である、項目４９または５０に記載の方法。
（項目５５）
前記第２部分が、γ−ヒドロキシ酪酸（ＧＨＢ）、またはＧＨＢの類似体、誘導体もしくは改変体である、項目４９または５０に記載の方法。
（項目５６）
前記第１および前記第２部分が、エステル結合、アミド結合、イミン結合、カルバメート結合、カーボネート結合、チオエステル結合、アシルオキシカルバメート結合、アシルオキシカーボネート結合、ホスフェート結合およびアシルオキシホスフェート結合からなる群より選択される共有結合によって連結されている、項目４９または５０に記載の方法。
（項目５７）
前記第１部分を前記第２部分に共有結合させるリンカーをさらに含む、項目４９または５０に記載の方法。
（項目５８）
前記リンカーが生理学的に不安定である、項目５７に記載の方法。
（項目５９）
前記化合物の第１部分または第２部分にイオン結合または共有結合された第３部分をさらに含む、項目４９または５０に記載の方法。
（項目６０）
前記化合物が少なくとも１種類の他の治療用薬剤と組み合わせて使用され得る、項目４９または５０に記載の方法。
（項目６１）
前記治療用薬剤が、抗精神病薬、抗不安薬、抗鬱薬、抗痙攣薬、抗パーキンソン病薬、アセチルコリンエステラーゼ阻害薬、ＭＡＯ阻害薬、選択的セロトニン再取込み阻害薬（ＳＳＲＩ）、Ｎ−メチル−Ｄ−アスパラギン酸（ＮＭＤＡ）拮抗薬、および選択的ノルアドレナリン置換阻害薬からなる群より選択される、項目６０に記載の方法。
（項目６２）
前記低減を必要とする被検体に、前記化合物と薬学的に許容され得る担体とを含む医薬組成物の治療有効量を投与することをさらに含む、項目４９または５０に記載の方法。
（項目６３）
前記障害が、疼痛または神経系疾患または障害である、項目４９または５０に記載の方法。
（項目６４）
前記疼痛が、急性、慢性または炎症性状態のものである、項目６３に記載の方法。
（項目６５）
前記神経系障害が、有痛障害、不安障害、鬱、解離性障害、人格障害、認知障害、気分障害、情動障害、神経変性障害、痙攣性障害、パーキンソン病、アルツハイマー病、癲癇、統合失調症、パラノイア、精神病、ハンティングトン病、ジル・ド・ラ・ツレット症候群、失神発作、運動低下症、脳障害、神経変性障害、パニック、不眠症、中毒性障害、および不穏下肢症候群からなる群より選択される、項目６３に記載の方法。
（項目６６）
前記被検体がヒトである、項目４９または５０に記載の方法。
（項目６７）
前記有害な副作用が、硬直、振せん、運動緩徐、精神緩慢、遅発性ジスキネジー、カタレプシー、急性ジストニア反応および静座不能（ａｋａｔｈａｓｉａ）からなる群より選択される、項目４９または５０に記載の方法。
（項目６８）
前記酸性末端がホスフィン酸基またはスルフィン酸基を含む、項目４９に記載の方法。
（項目６９）
前記保護基が、アミノ酸、イミン、カルバメート、Ｎ−ジチアスクシンイミド、モノ−もしくはジ−アルキルホスホルアミデート、またはアシルオキシカルバメートを含む、項目５０に記載の方法。
（項目７０）
前記保護基が前記第１部分のアミノ基から切断可能である、項目５０に記載の方法。
（項目７１）
障害の処置の治療有効性を向上させるための方法であって、該処置を必要とする被検体に治療有効量の化合物を投与することを含み、該化合物が、第１部分と第２部分とを含み、該第１部分は、アミノ末端またはカルボン酸基以外の酸性末端によって該第２部分に共有結合され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体である、方法。
（項目７２）
障害の処置の治療有効性を向上させるための方法であって、該処置を必要とする被検体に治療有効量の化合物を投与することを含み、該化合物が、第１部分と第２部分とを含み、該第１部分はカルボン酸基によって該第２部分に共有結合され、該第１部分のアミノ末端が保護基に連結され、該第１部分がγ−アミノ酪酸（ＧＡＢＡ）またはＧＡＢＡの類似体もしくは誘導体であるもの、方法。
（項目７３）
前記第１部分がＧＡＢＡ類似体である、項目７１または７２に記載の方法。
（項目７４）
前記第１部分が、バクロフェン、ビガバトリン、ガバペンチン、またはプレガバリンである、項目７１または７２に記載の方法。
（項目７５）
前記第２部分が鎮痛薬である、項目７１または７２に記載の方法。
（項目７６）
前記第２部分が、非ステロイド系抗炎症薬（ＮＳＡＩＤ）、オピオイド、または抗鬱薬である、項目７１または７２に記載の方法。
（項目７７）
前記第２部分が、γ−ヒドロキシ酪酸（ＧＨＢ）、またはＧＨＢの類似体、誘導体もしくは改変体である、項目７１または７２に記載の方法。
（項目７８）
前記第１および前記第２部分が、エステル結合、アミド結合、イミン結合、カルバメート結合、カーボネート結合、チオエステル結合、アシルオキシカルバメート結合、アシルオキシカーボネート結合、ホスフェート結合およびアシルオキシホスフェート結合からなる群より選択される共有結合によって連結されている、項目７１または７２に記載の方法。
（項目７９）
前記第１部分を前記第２部分に共有結合させるリンカーをさらに含む、項目７１または７２に記載の方法。
（項目８０）
前記リンカーが生理学的に不安定である、項目７９に記載の方法。
（項目８１）
前記化合物の第１部分または第２部分にイオン結合または共有結合された第３部分をさらに含む、項目７１または７２に記載の方法。
（項目８２）
前記化合物が少なくとも１種類の他の治療用薬剤と組み合わせて使用され得る、項目７１または７２に記載の方法。
（項目８３）
前記治療用薬剤が、抗精神病薬、抗不安薬、抗鬱薬、抗痙攣薬、抗パーキンソン病薬、アセチルコリンエステラーゼ阻害薬、ＭＡＯ阻害薬、選択的セロトニン再取込み阻害薬（ＳＳＲＩ）、Ｎ−メチル−Ｄ−アスパラギン酸（ＮＭＤＡ）拮抗薬、および選択的ノルアドレナリン置換阻害薬からなる群より選択される、項目８２に記載の方法。
（項目８４）
前記他の治療用薬剤が、前記化合物の投与の前、同時または後に投与される、項目８２に記載の方法。
（項目８５）
前記処置を必要とする被検体に、前記化合物と薬学的に許容され得る担体とを含む医薬組成物の治療有効量を投与することをさらに含む、項目７１または７２に記載の方法。
（項目８６）
前記障害が、疼痛または神経系疾患または障害である、項目７１または７２に記載の方法。
（項目８７）
前記疼痛が、急性、慢性または炎症性状態のものである、項目８６に記載の方法。
（項目８８）
前記神経系障害が、有痛障害、不安障害、鬱、解離性障害、人格障害、認知障害、気分障害、情動障害、神経変性障害、痙攣性障害、パーキンソン病、アルツハイマー病、癲癇、統合失調症、パラノイア、精神病、ハンティングトン病、ジル・ド・ラ・ツレット症候群、失神発作、運動低下症、脳障害、神経変性障害、パニック、不眠症、中毒性障害、および不穏下肢症候群からなる群より選択される、項目８６に記載の方法。
（項目８９）
前記被検体がヒトである、項目７１または７２に記載の方法。
（項目９０）
治療有効性の向上が、前記化合物の吸収の増大または半減期の増大によるものである、項目７１または７２に記載の方法。
（項目９１）
前記酸性末端がホスフィン酸基またはスルフィン酸基を含む、項目７１に記載の方法。
（項目９２）
前記保護基が、アミノ酸、イミン、カルバメート、Ｎ−ジチアスクシンイミド、モノ−もしくはジ−アルキルホスホルアミデート、またはアシルオキシカルバメートを含む、項目７２に記載の方法。
（項目９３）
前記保護基が前記第１部分のアミノ基から切断可能である、項目７２に記載の方法。
Furthermore, in the present invention, a kit for preventing or treating pain or nervous system disorders in a subject, comprising a compound of the present invention or a pharmaceutical composition of the compound of the present invention, and instructions for using the kit. provide. In some embodiments, the subject is an animal, preferably a human. In other embodiments, the kit is further for use in the treatment of pain or nervous system disorders, for reducing side effects induced by the compounds of the invention, and / or for the therapeutic efficacy of the compounds of the invention. Contains at least one other agent for improvement.
For example, the present invention provides the following items.
(Item 1)
A compound comprising a first portion and a second portion, wherein the first portion is covalently bonded to the second portion by an amino terminus or an acidic terminus other than a carboxylic acid group, and the first portion is γ-aminobutyric acid ( GABA) or an analog or derivative of GABA.
(Item 2)
Comprising a first portion and a second portion, wherein the first portion is covalently linked to the second portion by a carboxylic acid group, the amino terminus of the first portion is linked to a protecting group, and the first portion is γ- A compound that is aminobutyric acid (GABA) or an analog or derivative of GABA.
(Item 3)
3. A compound according to item 1 or 2, wherein the first part is a GABA analogue.
(Item 4)
Item 4. The compound according to Item 3, wherein the first moiety is baclofen, vigabatrin, gabapentin, or pregabalin, or a γ-aminophosphinic acid derivative.
(Item 5)
3. A compound according to item 1 or 2, wherein the second part is an analgesic.
(Item 6)
6. A compound according to item 5, wherein the second part is a nonsteroidal anti-inflammatory drug (NSAID), opioid, or antidepressant.
(Item 7)
3. A compound according to item 1 or 2, wherein the second part is γ-hydroxybutyric acid (GHB), or an analogue, derivative or variant of GHB.
(Item 8)
The first and second moieties are selected from the group consisting of ester bond, amide bond, imine bond, carbamate bond, carbonate bond, thioester bond, acyloxycarbamate bond, acyloxycarbonate bond, phosphate bond and acyloxyphosphate bond 3. A compound according to item 1 or 2 linked by a bond.
(Item 9)
Item 3. The compound of item 1 or 2, further comprising a linker that covalently bonds the first portion to the second portion.
(Item 10)
10. A compound according to item 9, wherein the linker is physiologically unstable.
(Item 11)
3. A compound according to item 1 or 2, further comprising a third portion that is ionically or covalently bound to the first or second portion of the compound.
(Item 12)
3. A compound according to item 1 or 2, which can be used in combination with at least one other therapeutic agent.
(Item 13)
The therapeutic agent is an antipsychotic, anxiolytic, antidepressant, anticonvulsant, antiparkinsonian, acetylcholinesterase inhibitor, MAO inhibitor, selective serotonin reuptake inhibitor (SSRI), N-methyl- 13. A compound according to item 12, selected from the group consisting of a D-aspartic acid (NMDA) antagonist and a selective noradrenaline replacement inhibitor.
(Item 14)
Item 2. The compound according to Item 1, wherein the acidic terminus includes a phosphinic acid group or a sulfinic acid group.
(Item 15)
Item 3. The compound of item 2, wherein the protecting group comprises an amino acid, imine, carbamate, N-dithiasuccinimide, mono- or di-alkyl phosphoramidate, or acyloxycarbamate.
(Item 16)
Item 3. The compound of item 2, wherein the protecting group is cleavable from the amino group of the first moiety.
(Item 17)
A pharmaceutical composition comprising the compound according to item 1 or 2 and a pharmaceutically acceptable carrier.
(Item 18)
18. A pharmaceutical composition according to item 17, further comprising at least one other therapeutic agent.
(Item 19)
Item 18. The pharmaceutical composition according to item 17, which is for treating pain and / or nervous system disorder.
(Item 20)
A kit for preventing or treating pain or a nervous system disorder in a subject, comprising the compound according to item 1 or 2, and instructions for using the kit.
(Item 21)
Item 21. The kit according to Item 20, wherein the subject is an animal, preferably a human.
(Item 22)
21. A kit according to item 20, further comprising at least one other agent for use in the treatment of pain or nervous system disorders.
(Item 23)
A method for the prevention or treatment of a disorder comprising administering a therapeutically effective amount of a compound to a subject in need of the prevention or treatment, the compound comprising a first part and a second part, A method wherein one moiety is covalently linked to a second moiety by an amino terminus or an acidic terminus other than a carboxylic acid group, wherein the first moiety is γ-aminobutyric acid (GABA) or an analog or derivative of GABA.
(Item 24)
A method for the prevention or treatment of a disorder comprising administering a therapeutically effective amount of a compound to a subject in need of the prevention or treatment, the compound comprising a first part and a second part, One part is covalently linked to the second part by a carboxylic acid group, the amino terminus of the first part is linked to a protecting group, and the first part is γ-aminobutyric acid (GABA) or an analog or derivative of GABA. There is a way.
(Item 25)
25. A method according to item 23 or 24, wherein the first part is a GABA analogue.
(Item 26)
25. A method according to item 23 or 24, wherein the first part is baclofen, vigabatrin, gabapentin, pregabalin, or a γ-aminophosphinic acid derivative.
(Item 27)
25. A method according to item 23 or 24, wherein the second part is an analgesic.
(Item 28)
25. A method according to item 23 or 24, wherein the second part is a non-steroidal anti-inflammatory drug (NSAID), opioid, or antidepressant.
(Item 29)
25. A method according to item 23 or 24, wherein the second part is γ-hydroxybutyric acid (GHB), or an analogue, derivative or variant of GHB.
(Item 30)
The first and second moieties are selected from the group consisting of ester bond, amide bond, imine bond, carbamate bond, carbonate bond, thioester bond, acyloxycarbamate bond, acyloxycarbonate bond, phosphate bond and acyloxyphosphate bond 25. A method according to item 23 or 24, which is linked by a bond.
(Item 31)
25. A method according to item 23 or 24, further comprising a linker that covalently bonds the first part to the second part.
(Item 32)
32. The method of item 31, wherein the linker is physiologically unstable.
(Item 33)
25. A method according to item 23 or 24, further comprising a third moiety ionic or covalently bonded to the first or second moiety of the compound.
(Item 34)
25. A method according to item 23 or 24, wherein the compound can be used in combination with at least one other therapeutic agent.
(Item 35)
The therapeutic agent is an antipsychotic, anxiolytic, antidepressant, anticonvulsant, antiparkinsonian, acetylcholinesterase inhibitor, MAO inhibitor, selective serotonin reuptake inhibitor (SSRI), N-methyl- 35. The method of item 34, wherein the method is selected from the group consisting of a D-aspartic acid (NMDA) antagonist and a selective noradrenaline replacement inhibitor.
(Item 36)
25. The method of item 23 or 24, further comprising administering to the subject in need of prevention or treatment a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
(Item 37)
25. A method according to item 23 or 24, wherein the disorder is pain or nervous system disorder.
(Item 38)
38. The method of item 37, wherein the pain is of an acute, chronic or inflammatory condition.
(Item 39)
The nervous system disorder is painful disorder, anxiety disorder, depression, dissociative disorder, personality disorder, cognitive disorder, mood disorder, affective disorder, neurodegenerative disorder, convulsive disorder, Parkinson's disease, Alzheimer's disease, epilepsy, schizophrenia , Paranoia, psychosis, Huntington's disease, Gilles de la Tourette syndrome, fainting, hypoxia, brain disorders, neurodegenerative disorders, panic, insomnia, addictive disorders, and restless leg syndrome 40. The method of item 37.
(Item 40)
25. A method according to item 23 or 24, wherein the subject is an animal.
(Item 41)
41. A method according to item 40, wherein the subject is a human.
(Item 42)
25. A method according to item 23 or 24, wherein administration of the compound or the pharmaceutical composition results in at least one side effect less than administration of the individual parts alone.
(Item 43)
25. A method according to item 23 or 24, wherein administration of said compound or said pharmaceutical composition results in improved therapeutic activity compared to administration of individual parts alone.
(Item 44)
25. A method according to item 23 or 24, wherein the compound or the pharmaceutical composition is administered in combination with another drug.
(Item 45)
45. The method of item 44, wherein said another agent is administered before, simultaneously with or after administration of said compound or said pharmaceutical composition.
(Item 46)
24. A method according to item 23, wherein the acidic terminal includes a phosphinic acid group or a sulfinic acid group.
(Item 47)
25. A method according to item 24, wherein the protecting group comprises an amino acid, imine, carbamate, N-dithiasuccinimide, mono- or di-alkyl phosphoramidate, or acyloxycarbamate.
(Item 48)
25. A method according to item 24, wherein the protecting group is cleavable from the amino group of the first portion.
(Item 49)
A method of reducing adverse effects associated with treatment of a disorder, comprising administering to a subject in need of said reduction a therapeutically effective amount of a compound, said compound comprising a first portion and a second portion. The first moiety is covalently linked to the second moiety by an amino terminus or an acidic terminus other than a carboxylic acid group, the first moiety being γ-aminobutyric acid (GABA) or an analog or derivative of GABA There is a way.
(Item 50)
A method of reducing adverse effects associated with treatment of a disorder, comprising administering a therapeutically effective amount of a compound to a subject in need of said reduction, said compound comprising a first portion and a second portion The first moiety is covalently bonded to the second moiety by a carboxylic acid group, the amino terminus of the first moiety is linked to a protecting group, and the first moiety is γ-aminobutyric acid (GABA) or GABA A method which is an analogue or derivative of
(Item 51)
51. A method according to item 49 or 50, wherein the first part is a GABA analog.
(Item 52)
51. A method according to item 49 or 50, wherein the first part is baclofen, vigabatrin, gabapentin, pregabalin, or a γ-aminophosphinic acid derivative.
(Item 53)
51. A method according to item 49 or 50, wherein the second part is an analgesic.
(Item 54)
51. The method of item 49 or 50, wherein the second portion is a non-steroidal anti-inflammatory drug (NSAID), opioid, or antidepressant.
(Item 55)
51. A method according to item 49 or 50, wherein the second part is γ-hydroxybutyric acid (GHB), or an analog, derivative or variant of GHB.
(Item 56)
The first and second moieties are selected from the group consisting of ester bond, amide bond, imine bond, carbamate bond, carbonate bond, thioester bond, acyloxycarbamate bond, acyloxycarbonate bond, phosphate bond and acyloxyphosphate bond 51. A method according to item 49 or 50, which is linked by a bond.
(Item 57)
51. The method of item 49 or 50, further comprising a linker that covalently bonds the first portion to the second portion.
(Item 58)
58. The method of item 57, wherein the linker is physiologically unstable.
(Item 59)
51. The method of item 49 or 50, further comprising a third moiety that is ionically or covalently bonded to the first or second moiety of the compound.
(Item 60)
51. The method of item 49 or 50, wherein the compound can be used in combination with at least one other therapeutic agent.
(Item 61)
The therapeutic agent is an antipsychotic, anxiolytic, antidepressant, anticonvulsant, antiparkinsonian, acetylcholinesterase inhibitor, MAO inhibitor, selective serotonin reuptake inhibitor (SSRI), N-methyl- 61. The method of item 60, wherein the method is selected from the group consisting of a D-aspartic acid (NMDA) antagonist and a selective noradrenaline replacement inhibitor.
(Item 62)
51. The method of item 49 or 50, further comprising administering to the subject in need of reduction a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
(Item 63)
51. A method according to item 49 or 50, wherein the disorder is pain or a nervous system disease or disorder.
(Item 64)
64. The method of item 63, wherein the pain is of an acute, chronic or inflammatory condition.
(Item 65)
The nervous system disorder is painful disorder, anxiety disorder, depression, dissociative disorder, personality disorder, cognitive disorder, mood disorder, affective disorder, neurodegenerative disorder, convulsive disorder, Parkinson's disease, Alzheimer's disease, epilepsy, schizophrenia , Paranoia, psychosis, Huntington's disease, Gilles de la Tourette syndrome, fainting, hypoxia, brain disorders, neurodegenerative disorders, panic, insomnia, addictive disorders, and restless leg syndrome 64. The method of item 63, wherein:
(Item 66)
51. A method according to item 49 or 50, wherein the subject is a human.
(Item 67)
51. The method of item 49 or 50, wherein the adverse side effect is selected from the group consisting of stiffness, tremor, slow movement, mental slowness, delayed dyskinesia, catalepsy, acute dystonia reaction and akathasia.
(Item 68)
50. The method of item 49, wherein the acidic terminus comprises a phosphinic acid group or a sulfinic acid group.
(Item 69)
51. The method of item 50, wherein the protecting group comprises an amino acid, imine, carbamate, N-dithiasuccinimide, mono- or di-alkyl phosphoramidate, or acyloxycarbamate.
(Item 70)
51. The method of item 50, wherein the protecting group is cleavable from the amino group of the first portion.
(Item 71)
A method for improving the therapeutic efficacy of a treatment for a disorder comprising administering a therapeutically effective amount of a compound to a subject in need of treatment, said compound comprising a first portion and a second portion. Wherein the first moiety is covalently linked to the second moiety by an amino terminus or an acidic terminus other than a carboxylic acid group, the first moiety being γ-aminobutyric acid (GABA) or an analog or derivative of GABA ,Method.
(Item 72)
A method for improving the therapeutic efficacy of a treatment for a disorder comprising administering a therapeutically effective amount of a compound to a subject in need of treatment, said compound comprising a first portion and a second portion. Wherein the first moiety is covalently bonded to the second moiety by a carboxylic acid group, the amino terminus of the first moiety is linked to a protecting group, and the first moiety is γ-aminobutyric acid (GABA) or GABA Those that are analogues or derivatives, methods.
(Item 73)
73. A method according to item 71 or 72, wherein the first part is a GABA analog.
(Item 74)
73. A method according to item 71 or 72, wherein the first part is baclofen, vigabatrin, gabapentin, or pregabalin.
(Item 75)
73. A method according to item 71 or 72, wherein the second part is an analgesic.
(Item 76)
73. A method according to item 71 or 72, wherein the second part is a nonsteroidal anti-inflammatory drug (NSAID), an opioid, or an antidepressant.
(Item 77)
73. A method according to item 71 or 72, wherein the second part is γ-hydroxybutyric acid (GHB), or an analog, derivative or variant of GHB.
(Item 78)
The first and second moieties are selected from the group consisting of ester bond, amide bond, imine bond, carbamate bond, carbonate bond, thioester bond, acyloxycarbamate bond, acyloxycarbonate bond, phosphate bond and acyloxyphosphate bond 73. A method according to item 71 or 72, which is linked by a bond.
(Item 79)
73. The method of item 71 or 72, further comprising a linker that covalently bonds the first portion to the second portion.
(Item 80)
80. The method of item 79, wherein the linker is physiologically unstable.
(Item 81)
73. A method according to item 71 or 72, further comprising a third portion ionically or covalently bound to the first portion or the second portion of the compound.
(Item 82)
73. A method according to item 71 or 72, wherein the compound can be used in combination with at least one other therapeutic agent.
(Item 83)
The therapeutic agent is an antipsychotic, anxiolytic, antidepressant, anticonvulsant, antiparkinsonian, acetylcholinesterase inhibitor, MAO inhibitor, selective serotonin reuptake inhibitor (SSRI), N-methyl- 84. The method of item 82, selected from the group consisting of D-aspartic acid (NMDA) antagonists and selective noradrenaline replacement inhibitors.
(Item 84)
84. The method of item 82, wherein the other therapeutic agent is administered before, simultaneously with, or after administration of the compound.
(Item 85)
73. The method of item 71 or 72, further comprising administering to the subject in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
(Item 86)
73. A method according to item 71 or 72, wherein the disorder is pain or a nervous system disease or disorder.
(Item 87)
90. The method of item 86, wherein the pain is of an acute, chronic or inflammatory condition.
(Item 88)
The nervous system disorder is painful disorder, anxiety disorder, depression, dissociative disorder, personality disorder, cognitive disorder, mood disorder, affective disorder, neurodegenerative disorder, convulsive disorder, Parkinson's disease, Alzheimer's disease, epilepsy, schizophrenia , Paranoia, psychosis, Huntington's disease, Gilles de la Tourette syndrome, fainting, hypoxia, brain disorders, neurodegenerative disorders, panic, insomnia, addictive disorders, and restless leg syndrome 90. The method of item 86.
(Item 89)
73. The method according to item 71 or 72, wherein the subject is a human.
(Item 90)
73. A method according to item 71 or 72, wherein the improvement in therapeutic efficacy is due to increased absorption or half-life of the compound.
(Item 91)
72. A method according to item 71, wherein the acidic terminal includes a phosphinic acid group or a sulfinic acid group.
(Item 92)
73. The method of item 72, wherein the protecting group comprises an amino acid, imine, carbamate, N-dithiasuccinimide, mono- or di-alkyl phosphoramidate, or acyloxycarbamate.
(Item 93)
73. A method according to item 72, wherein the protecting group is cleavable from the amino group of the first portion.
Claims (12)
（ｂ）前記ＧＡＢＡ類似体は、プレガバリン、ガバペンチン、バクロフェン、ビガバトリン、またはγ−アミノホスフィン酸の誘導体であるか；
（ｃ）前記鎮痛薬は、非ステロイド系抗炎症薬（ＮＳＡＩＤ）、オピオイド、または抗鬱薬であるか；
（ｄ）該第２部分は、γ−ヒドロキシ酪酸（ＧＨＢ）またはＧＨＢの類似体であるか；
（ｅ）該第１および該第２部分が、エステル結合、アミド結合、イミン結合、カルバメート結合、カーボネート結合、チオエステル結合、アシルオキシカルバメート結合、アシルオキシカーボネート結合、ホスフェート結合およびアシルオキシホスフェート結合からなる群より選択される共有結合によって連結されているか；
（ｆ）該第１部分を該第２部分に共有結合させるリンカーをさらに含むか；
（ｇ）該リンカーが生理学的に不安定であるか；
（ｈ）前記酸性末端がホスフィック（ｐｈｏｓｐｈｉｃ）酸基またはスルフィン酸基およびカルボン酸基を含むか；あるいは
（ｉ）該保護基が該第１部分のアミノ基から切断可能である、
請求項１〜８のいずれか一項に記載の化合物。 (A) the first part is covalently bonded to the second part by its carboxylic acid group, the amino terminus is linked to a protecting group, the protecting group comprising an amino acid, imine, carbamate, N-dithiasuccinimide, Contains mono- or di-alkyl phosphoramidates and acyloxycarbamates;
(B) the GABA analog is pregabalin, gabapentin, baclofen, vigabatrin, or a derivative of γ-aminophosphinic acid;
(C) the analgesic is a non-steroidal anti-inflammatory drug (NSAID), opioid, or antidepressant;
(D) the second part is γ-hydroxybutyric acid (GHB) or an analogue of GHB;
(E) The first and second moieties are selected from the group consisting of an ester bond, an amide bond, an imine bond, a carbamate bond, a carbonate bond, a thioester bond, an acyloxycarbamate bond, an acyloxycarbonate bond, a phosphate bond, and an acyloxyphosphate bond. Linked by a covalent bond;
(F) further comprises a linker that covalently bonds the first part to the second part;
(G) whether the linker is physiologically unstable;
(H) the acidic terminus comprises a phosphinic or sulfinic acid group and a carboxylic acid group; or
(I) the protecting group is cleavable from the amino group of the first moiety;
The compound as described in any one of Claims 1-8.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10380008P | 2008-10-08 | 2008-10-08 | |
| US61/103,800 | 2008-10-08 | ||
| PCT/US2009/060058 WO2010042759A2 (en) | 2008-10-08 | 2009-10-08 | Gaba conjugates and methods of use thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015032554A Division JP6167123B2 (en) | 2008-10-08 | 2015-02-23 | GABA conjugates and methods for their use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2012505238A JP2012505238A (en) | 2012-03-01 |
| JP2012505238A5 true JP2012505238A5 (en) | 2012-05-24 |
Family
ID=42101220
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011531180A Withdrawn JP2012505238A (en) | 2008-10-08 | 2009-10-08 | GABA conjugates and methods for their use |
| JP2015032554A Active JP6167123B2 (en) | 2008-10-08 | 2015-02-23 | GABA conjugates and methods for their use |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015032554A Active JP6167123B2 (en) | 2008-10-08 | 2015-02-23 | GABA conjugates and methods for their use |
Country Status (11)
| Country | Link |
|---|---|
| US (3) | US8268887B2 (en) |
| EP (2) | EP3075722A1 (en) |
| JP (2) | JP2012505238A (en) |
| KR (1) | KR101810246B1 (en) |
| CN (2) | CN102216257B (en) |
| AU (1) | AU2009302241B2 (en) |
| BR (1) | BRPI0919811B1 (en) |
| CA (1) | CA2740087C (en) |
| ES (1) | ES2589915T3 (en) |
| HK (1) | HK1220970A1 (en) |
| WO (1) | WO2010042759A2 (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8268887B2 (en) | 2008-10-08 | 2012-09-18 | Feng Xu | Drug conjugates and methods of use thereof |
| AU2010223045A1 (en) * | 2009-03-12 | 2011-11-03 | Luitpold Pharmaceuticals, Inc. | GABA-linked anthracycline-lipid conjugates |
| US8461197B2 (en) | 2009-04-23 | 2013-06-11 | Concert Pharmaceuticals, Inc. | 4-hydroxybutyric acid analogs |
| US20120046272A1 (en) * | 2010-08-23 | 2012-02-23 | Grunenthal Gmbh | Novel Therapeutic Compounds |
| ES2804540T3 (en) * | 2011-02-14 | 2021-02-08 | Concert Pharmaceuticals Inc | Deuterated analogs of 4-hydroxybutyric acid |
| WO2012161798A1 (en) * | 2011-02-25 | 2012-11-29 | Catabasis Pharmaceuticals, Inc. | Fatty acid gamma aminobutyric acid (gaba) conjugates and their uses |
| CN103193669B (en) * | 2013-02-27 | 2014-10-01 | 南京医科大学 | nNOS-Capon uncoupling compound, preparation method and application thereof |
| JP6766036B2 (en) * | 2014-06-02 | 2020-10-07 | ケトゲン インコーポレイテッド | Compounds for the treatment of seizures and other central nervous system disorders and conditions |
| US20180369174A1 (en) * | 2015-12-16 | 2018-12-27 | Achelios Therapeutics, Inc. | Methods and compositions for treating peripheral neuropathy |
| CN105777586A (en) * | 2016-04-14 | 2016-07-20 | 安徽省逸欣铭医药科技有限公司 | S(+)vigabatrin ester derivative and preparation method and application thereof |
| UY37341A (en) | 2016-07-22 | 2017-11-30 | Flamel Ireland Ltd | FORMULATIONS OF GAMMA-MODIFIED RELEASE HYDROXIBUTIRATE WITH IMPROVED PHARMACOCINETICS |
| US11504347B1 (en) | 2016-07-22 | 2022-11-22 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11602513B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11602512B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| EP3528784B1 (en) | 2016-10-21 | 2023-08-02 | APIRX Pharmaceutical USA, LLC | Suppositories comprising cannabinoids |
| FI3698791T3 (en) * | 2017-02-02 | 2024-01-11 | Otolanum Ag | Intranasal composition comprising betahistine |
| BR112020022885A2 (en) * | 2018-05-14 | 2021-03-23 | Xgene Pharmaceutical Inc. | crystalline forms of 1- (acyloxy) -alkyl carbamate drug conjugates of naproxen and pregabalin |
| CN108863873A (en) * | 2018-06-26 | 2018-11-23 | 台州学院 | A kind of sulphur allyl carbonate esters compound and preparation method thereof |
| KR102107304B1 (en) * | 2018-08-24 | 2020-05-06 | (주)엠앤씨생명과학 | Natural liposome comprising red yeast rice, process for the preparation thereof, and food composition comprising the same |
| CA3127871A1 (en) | 2019-03-01 | 2020-09-10 | Flamel Ireland Limited | Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state |
| US20230110028A1 (en) * | 2021-08-11 | 2023-04-13 | Tris Pharma, Inc. | Oxybate polyethylene glycol prodrugs |
| CN114452256A (en) * | 2021-12-31 | 2022-05-10 | 浙江大学 | Spinal cord injury targeted drug, polymer-hydrophobic compound micelle and preparation method thereof |
| US11779557B1 (en) | 2022-02-07 | 2023-10-10 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11583510B1 (en) | 2022-02-07 | 2023-02-21 | Flamel Ireland Limited | Methods of administering gamma hydroxybutyrate formulations after a high-fat meal |
| WO2023215323A1 (en) * | 2022-05-02 | 2023-11-09 | The Regents Of The University Of California | Intranasal baclofen |
| CN116585298A (en) * | 2023-06-30 | 2023-08-15 | 江苏海洋大学 | Coupling medicine, composition and application thereof |
Family Cites Families (59)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US404175A (en) | 1889-05-28 | O g o o o | ||
| US3625214A (en) | 1970-05-18 | 1971-12-07 | Alza Corp | Drug-delivery device |
| US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
| US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
| DE2460891C2 (en) | 1974-12-21 | 1982-09-23 | Gödecke AG, 1000 Berlin | 1-aminomethyl-1-cycloalkaneacetic acids and their esters, processes for their preparation and medicaments containing these compounds |
| IL67445A (en) * | 1982-12-09 | 1985-11-29 | Teva Pharma | Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids |
| US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
| EP0130119B1 (en) | 1983-06-23 | 1988-11-09 | Merck & Co. Inc. | (acyloxyalkoxy) carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs, their preparation and pharmaceutical compositions containing said derivatives |
| US4789734A (en) | 1985-08-06 | 1988-12-06 | La Jolla Cancer Research Foundation | Vitronectin specific cell receptor derived from mammalian mesenchymal tissue |
| US5023252A (en) | 1985-12-04 | 1991-06-11 | Conrex Pharmaceutical Corporation | Transdermal and trans-membrane delivery of drugs |
| EP0237051B1 (en) | 1986-03-14 | 1991-05-02 | Fujisawa Pharmaceutical Co., Ltd. | Prodrug compounds, process for the preparation thereof and sustained release preparation comprising the same |
| CH671155A5 (en) | 1986-08-18 | 1989-08-15 | Clinical Technologies Ass | |
| US5075109A (en) | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
| US5811128A (en) | 1986-10-24 | 1998-09-22 | Southern Research Institute | Method for oral or rectal delivery of microencapsulated vaccines and compositions therefor |
| US5001139A (en) | 1987-06-12 | 1991-03-19 | American Cyanamid Company | Enchancers for the transdermal flux of nivadipine |
| US4992445A (en) | 1987-06-12 | 1991-02-12 | American Cyanamid Co. | Transdermal delivery of pharmaceuticals |
| US4897268A (en) | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
| US5766573A (en) | 1988-12-06 | 1998-06-16 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| WO1992009560A1 (en) | 1990-11-27 | 1992-06-11 | Northwestern University | Gaba and l-glutamic acid analogs for antiseizure treatment |
| US6197819B1 (en) | 1990-11-27 | 2001-03-06 | Northwestern University | Gamma amino butyric acid analogs and optical isomers |
| US5190029A (en) | 1991-02-14 | 1993-03-02 | Virginia Commonwealth University | Formulation for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content |
| DK0641330T3 (en) | 1992-05-20 | 2001-12-03 | Univ Northwestern | Gaba and L-glutamic acid analogues for anticonvulsant therapy |
| US5376359A (en) | 1992-07-07 | 1994-12-27 | Glaxo, Inc. | Method of stabilizing aerosol formulations |
| JPH08505625A (en) | 1993-01-11 | 1996-06-18 | ダナ−ファーバー キャンサー インスティチュート | Induction of cytotoxic T lymphocyte response |
| ES2176668T3 (en) | 1996-02-07 | 2002-12-01 | Warner Lambert Co | NEW CYCLING AMINO ACIDS AS PHARMACEUTICAL AGENTS. |
| KR100512506B1 (en) | 1996-03-14 | 2005-12-21 | 워너-램버트 캄파니 엘엘씨 | Novel Substituted Cyclic Amino Acids as Pharmaceutical Agents |
| CZ287598A3 (en) | 1996-03-14 | 1999-02-17 | Warner-Lambert Company | Bridged cyclic amino acids |
| AU733896B2 (en) | 1996-10-23 | 2001-05-31 | Warner-Lambert Company | Substituted gamma aminobutyric acids as pharmaceutical agents |
| AU8668598A (en) | 1997-08-20 | 1999-03-08 | University Of Oklahoma, The | Gaba analogs to prevent and treat gastrointestinal damage |
| ATE311867T1 (en) | 1997-09-08 | 2005-12-15 | Warner Lambert Co | ANALGESIC COMPOSITION CONTAINING ANTEPILEPTIC DRUGS AND USES THEREOF |
| US6635673B1 (en) | 1997-10-27 | 2003-10-21 | Warner-Lambert Company | Cyclic amino acids and derivatives thereof useful as pharmaceutical agents |
| EP1047678B1 (en) | 1997-12-16 | 2004-09-08 | Warner-Lambert Company LLC | 1-substituted-1-aminomethyl-cycloalkane derivatives (=gabapentin analogues), their preparation and their use in the treatment of neurological disorders |
| TR200001800T2 (en) | 1997-12-16 | 2001-03-21 | Warner-Lambert Company | -4 (3) -Substituted -4 (3) - aminomethyl- (thio) pyran or- piperidine derivatives (= Gabapentin analogs), their preparation and use in the treatment of neurological diseases |
| KR20010033154A (en) | 1997-12-16 | 2001-04-25 | 로즈 암스트롱, 크리스틴 에이. 트러트웨인 | Novel Amines as Pharmaceutical Agents |
| NZ506793A (en) | 1998-05-26 | 2003-03-28 | Warner Lambert Co | Conformationally constrained amino acid compounds and their use for treating epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain and neuropathological disorders |
| GB9819926D0 (en) | 1998-09-14 | 1998-11-04 | Mead Corp | A tray container and blank |
| AU5478799A (en) | 1998-09-14 | 2000-04-03 | Warner-Lambert Company | Branched alkyl pyrrolidine-3-carboxylic acids |
| AU1602100A (en) | 1998-11-25 | 2000-06-13 | Warner-Lambert Company | Improved gamma amino butyric acid analogs |
| EP1031350A1 (en) | 1999-02-23 | 2000-08-30 | Warner-Lambert Company | Use of a gabapentin-analog for the manufacture of a medicament for preventing and treating visceral pain |
| EP1161263A1 (en) | 1999-03-10 | 2001-12-12 | Warner-Lambert Company Llc | Analgesic compositions comprising anti-epileptic compounds and methods of using same |
| JP3909842B2 (en) | 2000-06-26 | 2007-04-25 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | Gabapentin analogs for sleep disorders |
| EP1709957A3 (en) | 2001-06-05 | 2007-02-14 | Control Delivery Systems | Sustained-release analgesic compounds |
| US6818787B2 (en) * | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| KR20100097224A (en) * | 2001-09-27 | 2010-09-02 | 라모트 앳 텔 아비브 유니버시티 리미티드 | Conjugated anti-psychotic drugs and uses thereof |
| US7544681B2 (en) | 2001-09-27 | 2009-06-09 | Ramot At Tel Aviv University Ltd. | Conjugated psychotropic drugs and uses thereof |
| US7045543B2 (en) | 2001-11-05 | 2006-05-16 | Enzrel Inc. | Covalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites |
| ITMI20022658A1 (en) | 2002-12-17 | 2004-06-18 | Nicox Sa | DRUGS FOR CHRONIC PAIN. |
| GB0405200D0 (en) | 2004-03-08 | 2004-04-21 | Pfizer Ltd | Combinations comprising alpha-2-delta ligands |
| WO2005102390A2 (en) | 2004-04-22 | 2005-11-03 | Pfizer Japan, Inc. | Combinations comprising alpha-2-delta ligands and nmda receptor antagonists |
| JP2008536928A (en) | 2005-04-19 | 2008-09-11 | アルザ・コーポレーシヨン | A combination of tramadol and a substance comprising gabapentin |
| CN101247837B (en) * | 2005-06-07 | 2013-03-20 | 特拉维夫大学拉莫特有限公司 | Novel salts of conjugated psychotropic drugs and processes of preparing same |
| US7994220B2 (en) | 2005-09-28 | 2011-08-09 | Cypress Bioscience, Inc. | Milnacipran for the long-term treatment of fibromyalgia syndrome |
| MXPA05011735A (en) | 2005-11-01 | 2007-04-30 | Leopoldo Espinosa Abdala | Pharmaceutical compositions combining analgesics and anticonvulsant agents for the treatment of chronic and acute pain. |
| EP1820502A1 (en) | 2006-02-10 | 2007-08-22 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising azolylcarbinol compounds |
| AU2007274583B2 (en) * | 2006-07-17 | 2012-11-01 | Bar-Ilan University | Conjugates comprising a psychotropic drug or a GABA agonist and an organic acid and their use in treating pain and other CNS disorders |
| WO2008011016A2 (en) | 2006-07-18 | 2008-01-24 | Dynogen Pharmaceuticals, Inc. | Treating gastroesophageal reflux disease with 5-ht3- and gaba receptor agonists |
| WO2008009663A1 (en) | 2006-07-19 | 2008-01-24 | Boehringer Ingelheim International Gmbh | Treatment of pain |
| EP2101752A1 (en) * | 2006-12-08 | 2009-09-23 | Xenoport, Inc. | Use of prodrugs of gaba analogs for treating diseases |
| US8268887B2 (en) | 2008-10-08 | 2012-09-18 | Feng Xu | Drug conjugates and methods of use thereof |
-
2009
- 2009-10-08 US US12/576,136 patent/US8268887B2/en active Active
- 2009-10-08 AU AU2009302241A patent/AU2009302241B2/en active Active
- 2009-10-08 JP JP2011531180A patent/JP2012505238A/en not_active Withdrawn
- 2009-10-08 EP EP16159660.6A patent/EP3075722A1/en not_active Withdrawn
- 2009-10-08 CN CN200980145237.6A patent/CN102216257B/en active Active
- 2009-10-08 BR BRPI0919811-3A patent/BRPI0919811B1/en active IP Right Grant
- 2009-10-08 EP EP09819911.0A patent/EP2344447B1/en active Active
- 2009-10-08 CN CN201510667046.3A patent/CN105330603A/en active Pending
- 2009-10-08 WO PCT/US2009/060058 patent/WO2010042759A2/en active Application Filing
- 2009-10-08 ES ES09819911.0T patent/ES2589915T3/en active Active
- 2009-10-08 KR KR1020117010420A patent/KR101810246B1/en active IP Right Grant
- 2009-10-08 CA CA2740087A patent/CA2740087C/en active Active
-
2012
- 2012-08-09 US US13/571,268 patent/US9186341B2/en active Active
-
2015
- 2015-02-23 JP JP2015032554A patent/JP6167123B2/en active Active
- 2015-10-09 US US14/879,752 patent/US10478412B2/en active Active
-
2016
- 2016-07-28 HK HK16109028.9A patent/HK1220970A1/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2012505238A5 (en) | ||
| US8377990B2 (en) | Conjugates comprising a psychotropic drug or a GABA agonist and an organic acid and their use in treating pain and other CNS disorders | |
| AU765038B2 (en) | Method for the treatment of insomnia | |
| CA2386297A1 (en) | Bicyclic amino acids as pharmaceutical agents | |
| JP2011529923A5 (en) | ||
| EA200970287A1 (en) | METHODS, COMPOUNDS, COMPOSITIONS AND MEDIA SUITABLE FOR DELIVERY OF 3-AMINO-1-PROPANSULPHONE ACID | |
| US10493069B2 (en) | Methods of treating behavioral syndromes using pipradrol | |
| MX2012012225A (en) | Nitric oxide releasing prodrugs of therapeutic agents. | |
| RU2009145541A (en) | THERAPEUTIC COMPOUNDS | |
| JP2003506407A5 (en) | ||
| JP2005529840A5 (en) | ||
| UA112654C2 (en) | Methylphenidate-prodrugs, processes of making and using the same | |
| JP2010526827A5 (en) | ||
| WO2007143185A3 (en) | Transdermal treatment of tendinopathy using glyceryl trinitrite | |
| BRPI0513337A (en) | composition and process for improved bioavailability and better brain application of 5,5-diphenyl barbituric acid | |
| HRP20230745T3 (en) | Morphinan compounds | |
| RU2009145537A (en) | THERAPEUTIC COMPOUNDS | |
| AU2019268209B2 (en) | Compounds for the treatment of seizures and other central nervous system disorders and conditions | |
| KR20010071776A (en) | Pharmaceutical Composition Containing GABA Analogs and an Antiviral Agent to Treat Shingles | |
| AR071045A1 (en) | STEREO ISOMERO DE METIL- (2-HIDROXI-5- (((2- (4-HIDROXIFENIL) -1-METTILETIL) AMINO) ETIL) PHENYL) - CARBAMATE, MIXTURE OF ITS ISOMERS, PREPARATION PROCESS OF THE SAME, A PHARMACEUTICAL COMPOSITION CONTAINING SUCH CARBAMATE AND USE OF THE SAME | |
| JP2019073507A5 (en) | ||
| MXPA00011509A (en) | Method for the treatment of insomnia | |
| RU2007136824A (en) | MEDICINES OF AMPHETAMINE PROTECTED FROM IMPROPER USE | |
| RU2018137304A (en) | METHODS AND COMPOSITIONS FOR DELIVERY TO THE CNS ARILSULFATASE A | |
| JP2002520278A (en) | Treatment of renal colic with GABA analogs |